This part of the grant proposal involves the synthesis and formulation of a novel class of biodegradable polymers - polyanhydrides. Our research group will develop systems for releasing those substances desired by other research groups in the NCDDG using approaches developed in our laboratory and conduct research to create polyanhydrides that can encapsulate proteins and to release multiple drugs, and to release drugs for longer times. We will also explore new methods to create nanospheres. This work builds on earlier studies in which we proposed the first approaches for the synthesis of new biodegradable polymers that would display surface erosion (this would make the erosion process constant (for slabs) and predictable and had heretofore not been accomplished with biocompatible polymers without additives). Our proposal was that this might be achieved by synthesizing hydrophobic polyanhydrides. We developed new synthesis procedures for polyanhydrides and obtained the first high molecular weight (Mw>40,OOO) polyanhydrides; synthesized polyanhydrides, which can, by the choice of copolymer, degrade at different rates; developed microencapsulation approaches for these polymers and conducted toxicology studies on this class of polymers. All of these studies have led to the point where these are one of the very few synthetic biodegradable polymers and the only surface eroding polymer that are to be used as implants in clinical studies. In the past grant period, we successfully achieved our specific objectives. The last proposal had three specific aims: l) synthesis of polyanhydrides, 2) development of methods to incorporate substances in polyanhydride discs or pellets, and 3) development of microencapsulation approaches for polyanhydrides. Thirty-one papers were published on these topics. The specific aims of the current proposal are to l) develop approaches for creating nanospheres, 2) develop delivery systems for proteins, 3) develop systems that can release molecules from l month to l year, and develop systems to release multiple drugs.